Source Citation

Abstract

Question

In patients with unstable angina or non–ST-segment elevation myocardial infarction
(MI), is fondaparinux noninferior to enoxaparin for reducing death, MI, or refractory
ischemia and superior for reducing major bleeding?

Outcomes: A composite endpoint of death, MI, or refractory ischemia and major bleeding at 9
days. Secondary outcomes included individual outcomes at 30 and 180 days.

Patient follow-up: 99.9% (intention-to-treat analysis).

Main results

Fondaparinux was noninferior to enoxaparin for the primary composite endpoint and
death or MI was superior for reducing death at 30 and 180 days; and led to a lower
incidence of major bleeding (Table).

Conclusions

In patients with unstable angina or non–ST-segment elevation myocardial infarction,
fondaparinux was noninferior to enoxaparin for reducing death, MI, and refractory
ischemia. Fondaparinux decreased risk for major bleeding.

‡MI = myocardial infarction. Other abbreviations defined in Glossary; difference, RRR, NNT, and CI calculated from hazard ratios in article.§Death, MI, or refractory ischemia.&Verbar;Criteria for noninferiority were met because the upper limit of the CI
was < prespecified delta margin of 1.185.

Commentary

How does one make sense of trials where a difference is shown, but it might be due
to different drug products, different routes of administration, different anticoagulation
effects, and different durations of therapy?

In the ExTRACT-TIMI trial by Antman and colleagues, the only unbiased comparison was
at 48 hours, when both groups were receiving treatment. At that time, the slight,
albeit nonsignificant, reduction in the primary endpoint (5 per 100) with enoxaparin
was counterbalanced with an increase in major bleeding (4 per 100). Thereafter, enoxaparin
was associated with prevention of nonfatal MI at the cost of increased major bleeding.
However, at 30 days, the net clinical benefit still favored enoxaparin. Ultimately,
for every 3 nonfatal MI events prevented, 1 major bleed was caused by enoxaparin.
Moreover, more patients with major bleeding died on enoxaparin than on standard UFH.

Data on the degree of anticoagulation (e.g., target partial thromboplastin times or
anti-Xa levels) and bleeding risk for patients > 75 years of age would be
of interest. Previous studies suggested that usual enoxaparin dosing regimens were
associated with increased risk for major bleeding in older patients (1). In the ExTRACT-TIMI trial, the enoxaparin dose was lower in older patients and
may confer less benefit. Low anti-Xa levels can also increase 30-day mortality (2).

Is there a role for enoxaparin up to hospital discharge? In the context of net clinical
benefit, this strategy has merit. Enoxaparin use should be avoided in patients with
renal failure, the morbidly obese, and older patients. In jurisdictions where primary
percutaneous coronary intervention is standard, clinicians will probably use heparin
with or without glycoprotein IIb/IIIa inhibitors in the cardiac catheterization laboratory.

The OASIS-5 trial by Yusuf and colleagues showed that fondaparinux was as effective
as enoxaparin for patients with ACSs without ST-segment elevation, but was associated
with lower bleeding risk. In other trials of antithrombotic regimens, clinicians have
faced trade-offs between a somewhat greater clinical benefit and an increased risk
for major bleeding—a price to pay for preventing additional cardiac events.

It is not surprising that fondaparinux was associated with less bleeding because a
“DVT prophylaxis” dose of fondaparinux was compared with a “therapeutic” dose of enoxaparin.
The effectiveness data are more surprising. If fondaparinux is as effective as enoxaparin,
why is there excess catheter-related thrombus? This is potentially important and suggests
that fondaparinux use during coronary intervention needs more study. Alternatively,
adjunctive periprocedural heparin may be required, which may increase bleeding risk
at the access site.

Could the results be explained by increased bleeding risk with enoxaparin rather than
decreased risk with fondaparinux? Perhaps, in part, considering that 61% of patients
in the OASIS-5 trial were ≥ 65 years of age. In the ASSENT-3 trial (admittedly
in patients treated with thrombolysis), there was an increased bleeding risk for those
≥ 75 years of age (1). As a result, the dose of enoxaparin was lowered for older patients in the ExTRACT-TIMI
trial. Simply lowering the dose of enoxaparin to reduce bleeding risk may not be the
answer because effectiveness has not been shown at lower doses. Furthermore, the fondaparinux
group had a lower risk for major bleeding in patients < 65 years of age.
Therefore, while older patients may have a potential disadvantage at the lower enoxaparin
dose, this may only partially explain the bleeding difference.

Major bleeding is important. In similar trials, major bleeding was associated with
increased mortality. In the OASIS-5 trial, all excess deaths in the enoxaparin group
were bleeding related. Although it was not possible to tell from this study whether
bleeding caused the increased deaths, data from other studies, including the ExTRACT-TIMI
trial, strongly suggest that it does.

Fondaparinux should definitely be used in patients with ACS. The once-daily fixed
dose may allow for fewer dosing errors (3), and the lower cost of fondaparinux will be attractive to clinicians and hospital
administrators. However, in jurisdictions where a routine aggressive early-intervention
approach is used, the potential for catheter-related thrombus may be of sufficient
concern that fondaparinux will not be considered. Instead, clinicians will use familiar
periprocedural antithrombotic strategies. It is possible that fondaparinux will be
used for patients with lower-risk ACS.

David Massel, MDLondon Health Sciences CenterLondon, Ontario, Canada

References

1. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin
enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of
the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial
in acute myocardial infarction. Circulation. 2003;108:135-42. [PubMed ID: 12847070]